Congenital or neonatal lung diseases cause considerable morbidity and mortality in infants and lead to life-long lung dysfunction and dyspnea in survivors. The emerging field of systems biology has great potential to illuminate the complex gene regulatory networks and interacting mechanisms that control normal lung development and go awry during abnormal development leading to disease. This approach first requires access to databases that define the genetic programs of lung development, yet to date no databases required by systems scientists have been prepared from pure human lung lineages during normal or diseased lung development. This proposal prepares the databases and initiates the analytical and computational approaches required to found a developmental systems biology study of lung child birth defects. We seek to understand normal and diseased human lung development by preparing the first dynamic human lung developmental databases of gene expression and global histone modifications using differentiation of induced pluripotent stem cells (iPSCs) in culture In this proposal, we bring together lung developmental biologists, stem cell biologists, clinicians, physicists, and computational researchers to apply this new in vitro model system to map the epigenome and transcriptome of normal human lung development and to construct gene regulatory networks of development using naturally occurring or engineered perturbations in NKX2.1 that are known to lead to lung birth defects. In aim 1, we define the global epigenomic and transcriptomic programs emerging during normal human lung development using a novel human embryonic stem cell (ESC)/iPSC in vitro model system able to recapitulate the developmental sequence of lung epithelial lineage specification and differentiation. In Aim 2 we identify dynamic candidate gene regulatory networks, histone-DNA interactions, and enhancer/promoter elements using time-series data obtained during the establishment of normal lung epithelial cell fate. In aim 3 we develop systems developmental biology approaches for understanding the pathogenesis of lung child birth defects using disease-specific iPSCs generated from children with lung birth defects.